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From the Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The chemokines have several functions but one of their major attributes is the ability to induce chemotaxis of neutrophils.5,6 With this property chemokines serve to bring these cells to sites of acute inflammation, and also to retain them once they have arrived. A portion of the mechanism responsible for this recruitment is the generation of a chemotactic/haptotactic gradient to draw the cells into the local environment.7 Previous reports have demonstrated that high intravascular levels of IL-8 will reduce neutrophil emigration to sites of local inflammation.8-10
Mice carrying the human IL-8 transgene have extremely high plasma levels of this chemokine.11 Rodent neutrophils will respond to human IL-8 by chemotaxis although a higher concentration is required.12 We sought to test whether continuous high plasma concentrations of IL-8 would reduce neutrophil recruitment in four different animal models of acute inflammation. Given the redundancy of chemokines1,2 we investigated whether the murine chemokines would become up-regulated to offset the high plasma IL-8 levels and allow recruitment of neutrophils to the sites of inflammation. To specifically test if local up-regulation of endogenous murine chemokines was responsible for neutrophil recruitment, we performed antibody inhibition studies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A breeding colony of mice was established from mice generously
donated by Scott Simonet of Amgen, Inc. (Thousand Oaks, CA). These mice
(HE8 line) carry the human IL-8 transgene and express high, systemic
levels of IL-8 in the plasma.11
Hybrid mice were obtained
by crossing the IL-8 transgenic mice with BDF1
mice (Charles Rivers, Portage, MI). At 
8 weeks of age the plasma
levels of IL-8 were determined by obtaining a small sample of blood
from the tail vein. IL-8 was determined using our previously described
enzyme-linked immunosorbent assay (ELISA).13
Mice were
divided on the basis of their plasma levels of IL-8 into negative mice
(IL-8-negative), which had undetectable levels of IL-8 (<200 pg/ml),
and positive mice (IL-8-positive), which had >90,000 pg/ml of IL-8. A
third group of mice was also evaluated, wild-type
BDF1. In the unmanipulated mice, a complete blood
count with differential was performed. Additionally, the lungs were
homogenized and the myeloperoxidase (MPO) content of the lung was
determined as a measure of neutrophil sequestration, as previously
described.14
Briefly, the chest cavity was exposed and the
right side of the heart perfused with 0.9% isotonic saline (normal
saline) to remove blood from pulmonary circulation. The right lung was
then removed and placed on ice in MPO homogenization buffer, the lung
was homogenized followed by sonication. After centrifugation the
supernatant was mixed with assay buffer and read in a kinetics mode on
an ELISA reader.
Models of Acute Inflammation
The experiments in this article were performed in accordance with National Institutes of Health guidelines and approval from the Animal Use Committee of the University of Michigan.
Cecal Ligation and Puncture (CLP)
CLP was performed as previously described with minor modifications.15,16 Mice were anesthetized with ketamine/xylazine (87 and 13 mg/kg of body weight, respectively) and a small midline abdominal incision was made. The cecum was isolated and punctured three times with a 16-gauge needle that resulted in 60 to 70% lethality. The needle was removed and a small amount of the stool was expelled from the punctures to ensure patency. The mice were closed using 4.0 sutures for the abdomen and stainless steel removable wound clips for the skin. After the surgery, mice were injected subcutaneously with 1 ml of prewarmed isotonic saline before being placed into their cage. Mice were treated with subcutaneous antibiotics (23 mg/kg of imipenem diluted in D5W) at 2 hours after surgery. This dose was repeated every 12 hours for a total of 3 days so that mice were receiving both antibiotics and fluids. Mice were kept in a temperature-controlled room (25°C) with light and dark cycles every 12 hours.
Collection of Data
Mice were sacrificed 24 hours after CLP, before they received their third antibiotic injection. At the time of sacrifice heparin anti-coagulated plasma was collected and stored for later cytokine analysis. A complete blood count was performed with a Coulter Counter (model Zf; Coulter Electronic, Hialeah, FL). Peritoneal washes were performed by opening the peritoneum sterilely and washing with 1 ml of 1x Hanks’ balanced salt solution. This was followed with a separate wash of 15 ml with 1x Hanks’ balanced salt solution. The 1-ml wash was centrifuged and supernatant was frozen for later analysis. Cells from the centrifugation were then combined with cells from the 15-ml wash. White blood cell differentials were obtained by staining with Diff-Quick (Baxter, Detroit, MI). The right lung was harvested for MPO determination. Blood was obtained from the tail vein and an automated differential was performed using a Hemavet Mascot (CDC Technologies, Oxford, CT) as previously described.17
Preparation of Recombinant Murine Chemokines and ELISAs
Recombinant murine KC and MIP-2 were prepared in a bacterial expression system and the recombinant protein isolated from glutathione-Sepharose columns (pGEX system; Pharmacia, Piscataway, NJ) as previously described.18,19 The purified KC or MIP-2 protein was >95% pure as judged by denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These purified proteins will induce neutrophil chemotaxis in mouse or human neutrophils and they were used to raise rabbit or goat polyclonal antibodies by immunization with Freund’s complete adjuvant or Titermax (Sigma Chemical Co., St. Louis, MO). The antibodies were used to prepare ELISAs for protein quantification using our previously published methods.13 These antibodies have specificity with no cross-reactivity in the ranges used.18 A polyclonal antibody to KC was also raised in a goat as previously described.19
Cytokine Analysis
Cytokines were measured in the peritoneal fluid, bronchoalveolar lavage, and plasma. Tumor necrosis factor (TNF) was determined by cytolytic activity directed against the WEHI 164 fibrosarcoma cells as previously described.20,21 The concentration of TNF was determined by calculation from a standard curve of recombinant human TNF (Cetus, Emmeryville, CA). IL-6 was measured by the B9 cell proliferation assay as previously described22 and the IL-6 concentrations determined from a standard curve of human recombinant IL-6. KC and MIP-2 were quantified by an ELISA developed in our laboratory according to our published methods.13,18 Briefly, polyclonal antibodies were purified on protein A columns and used as capture antibodies. A portion of the same antibody was biotinylated and used for the detection antibody. Streptavidin-HRP (Jackson Immunoresearch, West Grove, PA) was used for amplification and the color was developed with TMB solution (Genzyme, Cambridge, MA). Neutrophil chemotaxis was performed using a 48-well chemotaxis chamber (Neuroprobe, Cabin John, MD) and previously described methods.18,23 Neutrophils were prepared from the peripheral blood of either the IL-8-positive or IL-8-negative mice by dextran sedimentation and hypotonic lysis of residual red blood cells. Chemotaxis was expressed as the percentage of cells that migrated to 10-6 mol/L fMLP (Sigma), after background subtraction.
In Vitro Stimulation
Alveolar macrophages or peritoneal cells were harvested from either the IL-8-positive or IL-8-negative mice. The cells were incubated in RPMI 1640 with 1% fetal calf serum at a concentration of 1.5 x 105 cells/ml (alveolar macrophages) or 5 x 105 cells/ml (peritoneal cells). The cells were stimulated with 1 µg/ml of lipopolysaccharide and the supernatants collected after 24 hours.
Acid Lung Injury
Acid lung injury was induced by injection of 80 to 100 µl of diluted HCl, pH 1.5, following a previously described procedure.24,25 Isotonic 0.9% saline was diluted 1:3 and the pH adjusted to 1.5 with concentrated HCl. Mice were anesthetized with ketamine/xylazine, the mice vertically suspended and the trachea exposed. Under direct visualization, the acid was instilled into the trachea using a 30-gauge needle. This was done with multiple small injections with the animal spontaneously breathing between each injection. Control mice had 0.9% isotonic saline (normal saline) injected in place of diluted acid. Immediately after surgery the neck was closed with a stainless steel surgical clip. At the time of sacrifice, heparin anti-coagulated plasma was obtained and saved for cytokine analysis. The lungs were then lavaged with 1 ml of warmed Hanks’ balanced salt solution in 0.2- to 0.3-ml aliquots. This bronchoalveolar lavage fluid was centrifuged and the supernatant saved for cytokine analysis. The lungs were lavaged with a second ml of Hanks’ balance salt solution and the cell pellets combined. A cell count was performed, and a differential done on a Diff-Quik-stained cytospins.
Glycogen or Thioglycollate Peritonitis
Glycogen was prepared fresh as a 2% solution (oyster shell glycogen, Sigma) in sterile isotonic saline. Thioglycollate (2.9%; Difco, Detroit, MI) was prepared and autoclaved. Either thioglycollate or glycogen was injected intraperitoneally in a 1- to 2-ml volume, as previously described.18,19 Four hours later mice were sacrificed and the peritoneum washed as described in the CLP model. Heparin anti-coagulated plasma was also obtained.
Antibody Neutralization Studies
For these experiments mice were injected subcutaneously with 1 ml of 50:50 mixture of goat anti-KC plus rabbit anti-MIP-2. These antibodies have previously been described and will effectively neutralize murine chemokines in vivo.19 For controls, mice were injected with 1 ml of control goat serum plus control rabbit serum. Two hours later, the mice were injected with 2 ml of thioglycollate. Samples were harvested 4 hours later and the total number of peritoneal neutrophils determined as described above.
Statistical Analysis
The values for the IL-8-positive mice were compared to the IL-8-negative mice using the Student’s t-test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We evaluated several normal parameters to differentiate the
IL-8-positive mice from the IL-8-negative mice. First, the differences
in plasma levels of IL-8 were significantly different, but because this
was the criterion used to separate the two populations this was the
expected result. IL-8-positive mice had a significantly higher white
blood cell count because almost exclusively of the increased numbers of
neutrophils (Figure 1)
. In a separate
experiment, we examined the peripheral blood values of nontransgenic
mice and IL-8-negative mice. The absolute number of peripheral blood
neutrophils in the nontransgenic mice (2.37 ± 0.54 x
106
cells/ml) was nearly identical to the
IL-8-negative mice (2.35 ± 0.41 x 106
cells/ml). Pulmonary MPO demonstrated substantially more neutrophils
within the lung. Histological examination of the lungs showed that the
neutrophils were within the blood vessels and not in the alveolar
airspaces. These results confirm the previous report that the IL-8
transgenic mice have evidence of increased numbers of neutrophils both
in the circulating blood and within the tissues.11
They
also indicate that mice will respond to the human IL-8 transgene
because there are increased numbers of neutrophils.
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Mice were subjected to CLP and followed for 7 days. There was a
slightly better survival in the IL-8-positive mice, but this was not
significant based on log-rank survival analysis
(P > 0.05). In the IL-8-positive mice there
were 15 out of 34 survivors, whereas in the IL-8-negative mice there
were 10 out of 37 survivors. Because neutrophils represent a critical
component of the innate immune response to bacterial infections we
determined if there was adequate recruitment of neutrophils into the
peritoneum in response to severe inflammation. Mice were subjected to
CLP, treated with antibiotics, and sacrificed at 24 hours. Figure 2
shows that there was no difference
between the IL-8-positive and IL-8-negative mice with regards to the
total number of recruited neutrophils. There was also no difference in
the number of macrophages, lymphocytes, basophils, or eosinophils
recovered from the peritoneum.
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Aspiration of gastric contents may result in acute lung
injury.26
To mimic this scenario, we injected diluted HCl
(pH 1.5) intratracheally and then determined the number of neutrophils
recruited into the bronchoalveolar space. Examination of histological
sections showed that neutrophils were in the alveolar space. Kinetics
studies showed that in the first 8 hours there was a modest influx of
neutrophils, but by 15 hours >40% of the cells in the lavage fluid
were neutrophils. There were no significant differences between
IL-8-positive and IL-8-negative mice (P >
0.05). At the 0-hour time point there were no neutrophils recovered in
the bronchoalveolar lavage fluid. These findings are in contrast to the
total lung MPO data that showed greater activity in the IL-8-positive
mice (Figure 1)
. Alveolar neutrophil recruitment was examined more
closely in Figure 3
where the total
number of cells in the lung was quantitated. The number of neutrophils
was substantially greater in response to acid injection compared to
isotonic saline (normal saline), but there was no difference between
IL-8-positive and IL-8-negative mice.
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Intraperitoneal injection of thioglycollate has been widely used
for the elicitation of neutrophils in rodents.27
Mice were
sacrificed 4 hours after intraperitoneal injection (control mice
received isotonic saline) and the total number of peritoneal cells
determined. Isotonic saline injection resulted in virtually no
peritoneal neutrophil recruitment (Figure 4)
. These data parallel the lung data in
which intratracheal injection of isotonic saline did not result in
pulmonary neutrophil recruitment. Additionally, no detectable IL-8 was
present in the peritoneal lavage fluid from either the IL-8-negative or
IL-8-positive mice. In contrast, injection of either glycogen or
thioglycollate resulted in neutrophil recruitment. In both models there
were fewer neutrophils recruited in IL-8-positive mice similar to the
previous report using these mice,11
but this difference
was never statistically significant (P > 0.05).
We have previously shown that the peritoneal recruitment of neutrophils
in response to 3% thioglycollate is mediated by local production of
both KC and MIP-2.19
Thioglycollate injection did not
cause any increase in the local levels of IL-8, which is expected
because the IL-8 is under constitutive control.
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displays the data and demonstrates that there was no difference between
IL-8-negative and IL-8-positive mice. Table 1
also illustrates trends
in these different models of inflammation. CLP represents the greatest
inflammatory insult and has the highest levels of TNF and IL-6. It
should be noted that these samples were obtained at different times
after the onset of the injury and may not represent the peak values. In
general, local cytokine levels were higher than systemic levels with
the exception of CLP, as previously reported.28,29
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demonstrates
that there was no significant difference in the inherent ability of
IL-8-positive or IL-8-negative macrophages to produce the murine
chemokines.
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. Although KC
was more potent than IL-8 or MIP-2, the response of the neutrophils
from the IL-8-positive and IL-8-negative mice was equivalent. These
data indicate that the peripheral blood neutrophils from both groups of
mice have the capacity to move toward a chemotactic stimulus.
Therefore, if there were alterations in the CXCR2 chemokine receptor
these changes did not result in a decrease of neutrophil function as
measured by the chemotactic response.
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shows that both groups of mice have
striking up-regulation of chemokines within the peritoneal cavity. The
IL-8-positive mice, however, had significantly higher concentrations of
both KC and MIP-2 compared to the IL-8-negative mice, showing that
enhanced local production of these murine chemokines occurred. The
increased levels of these chemokines may represent the biological
response to overcome the IL-8 chemotactic gradient and effectively
recruit neutrophils to the sites of local inflammation.
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. The number of peritoneal neutrophils
was equivalent to those observed in the mice injected with normal
saline (thioglycollate + anti-chemokine = 42,000 total neutrophils
versus saline = 45,000 total neutrophils). These data
provide compelling evidence that the up-regulated murine chemokines
were responsible for the neutrophil recruitment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neutrophils are the signature cell of acute inflammation, and by extension IL-8 should only be involved in acute inflammatory processes. Nevertheless, IL-8 may persist for prolonged periods in tissue culture or stimulated whole blood.34 The persistence of IL-8 has also been documented in vivo in multiple studies. In chronic disease states, there are increased systemic levels of IL-8, including patients with HIV infections,35 or ß-thalassemia.36 In longitudinal studies, peripheral blood levels of IL-8 persisted throughout several days in patients with malaria.37 IL-8 stability has also been documented in local forms of inflammation. These data include finding IL-8 in lavage fluid for up to 7 days in patients who develop nosocomial pneumonia.29 IL-8 has been identified within empyema fluid,38 in patients with chronic lung diseases,39 and has been recovered from the joint fluid of patients with arthritis.40 High local levels of chemokines have been found in patients with lung inflammation such as acute respiratory distress syndrome41 and asthma.42 IL-8 has been found in the dialysate of patients on continuous peritoneal dialysis for up to 5 days,43 and within the colonic mucosa of patients with chronic ulcerative colitis.44 Ischemia/reperfusion injury to the heart will induce the formation of IL-8 mRNA in the myocardium and the mRNA will persist beyond 24 hours.45 Given all of this information it is apparent that IL-8 has the potential to be long lasting and neutrophils may need to move into a local site of inflammation in the face of prolonged, elevated plasma levels of IL-8.
Our data show that neutrophil recruitment to local sites of inflammation will take place in the setting of chronically elevated systemic levels of IL-8. A possible explanation for the failure of high plasma levels of IL-8 to prevent neutrophil recruitment is desensitization of the chemokine receptors. Desensitization occurs between the CXC chemokines so that previous exposure to one chemokine renders a cell refractory to stimulation with a second chemokine.46,47 Although this desensitization occurs in vitro with murine CXC chemokines,48 the in vivo chemokine/receptor interaction is more dynamic. The IL-8 receptor (CXCR1) is rapidly internalized after cell surface binding and is then re-expressed on the cell surface within 10 minutes.49 This chemokine receptor is now available for binding to the chemokine to exert its biological effect. Our data show that receptor desensitization has not occurred because neutrophils from IL-8-positive and IL-8-negative mice exhibit equal chemotaxis toward recombinant IL-8.
The failure of chronic elevated levels of IL-8 to reduce inflammation, and the specific failure to reduce neutrophil recruitment may be understood because of the complexity and redundancy of chemokines and their receptors. CXC chemokines represent important mediators for the influx of neutrophils to sites of acute inflammation.50,51 The precise participation of the chemokines is also complicated by the presence of multiple chemokine receptors with relative specificity for the different chemokines. In general, CXC chemokines only bind the CXC chemokine receptors.52 With the redundancy and overlap in chemokines, a complex in vivo focus of inflammation will involve multiple chemokines that would be available to recruit neutrophils.53-55 The exact murine homolog of human IL-8 has not been identified,56 but the two most probable candidates are either KC or MIP-2. Both of these chemokines will be rapidly up-regulated in a rodent model of acute lung injury.4 Our data show that high levels of both of these chemokines are found within the peritoneum after thiolglycollate injection, and that IL-8-positive mice had significantly higher levels than the IL-8-negative mice. The peritoneal chemokine levels were higher, and the number of recruited neutrophils in multiple experiments was essentially equivalent in the IL-8-positive and IL-8-negative mice. This suggests that enhanced local production of chemokines was the appropriate biological response to generate a sufficient chemotactic gradient to induce neutrophils to migrate toward the peritoneum against the IL-8 chemotactic gradient. To provide additional support for this concept we performed antibody inhibition studies in the IL-8-positive mice. Antibody inhibition of the endogenous murine chemokines resulted in a >90% reduction in the number of peritoneal neutrophils. We believe our data support the concept that redundancy in the inflammatory response helps to ensure local neutrophil recruitment.1,2
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Footnotes |
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Supported in part by National Institutes of Health grants GM 44918 and GM 50401.
Accepted for publication May 31, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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